In the formulation of medicinal products for the topical application of active substances the choice of excipients is of critical importance. It is known, for instance, that there is a correlation between the solubility of an active substance in a vehicle and its release from that vehicle. When a vehicle containing active substance is applied to the skin, an equilibrium is established in the partition of the active substance between vehicle and skin. The position of this equilibrium is determined by the solubility in both phases.
Transdermal therapeutic systems (TTS) for delivering active substances through the skin have been known for a long time. The topical application of drugs by way of active substance patch systems offers two main advantages: firstly this form of administration produces first-order release kinetics of the active substance, thereby enabling a constant level of active substance to be maintained in the body over a very long period. Secondly the path of uptake through the skin avoids the gastrointestinal tract and also the first liver passage. As a result, selected drugs can be administered effectively in a low dose. This is particularly advantageous when the drug is desired to act locally, with avoidance of a systemic effect. This is the case, for example, with the treatment of rheumatic joint complaints or muscular inflammation.
One embodiment of such transdermal systems which has been well described in the technical literature is that of matrix systems or monolithic systems in which the drug is incorporated directly into the pressure-sensitive adhesive. In the ready-to-apply product a pressure-sensitive adhesive matrix of this kind, comprising active substance, is equipped on one side with a backing, which is impermeable to the active substance, while on the opposite side there is a backing film equipped with a release layer, which is removed prior to application to the skin (Kleben & Dichten, No. 42, 1998, pp. 26 to 30). Thus mention is made principally of the use of polyacrylates and/or polyurethanes as a basis for the pressure-sensitively adhesive polymer matrix (Lambda, Woodhouse, & Cooper, “Polyurethanes in Biomedical Applications”, CRC Press, 1998, p. 240) and WO 01/68060.
A problem associated with the production of transdermal therapeutic systems is the introduction of polar active substances into the generally non-polar polymer matrices. As a result it is possible for preferred active substances to be incorporated sometimes only with difficulty or only in a limited concentration into the polymer matrix. The risk exists, moreover, that because of the difference in polarity and insolubility of the active substances in the polymer matrix, the active substances will, over time, crystallize out of the polymer system. Long-term stability is therefore not ensured.
One proposal for solving these problems is provided by the addition of solvent. The incorporation of solvent into a polymer matrix, however, has a variety of drawbacks. These include the harmful nature of the generally organic solvents, high levels of technical effort involved in suction extraction and recovery, high costs for the high-purity solvents that are necessary, and, in particular, a very high level of effort required for removing solvent residues from the matrix.
These solvents are likewise absorbed through the skin, thereby lowering the solvent content of the TTS matrix. Additionally it has been found that water given off by the skin accumulates in the solvent, since it cannot be readily bound by the hydrophobic polymer matrix. Both mechanisms result in an adverse effect on the release of active substance.
WO 01/68060 A2 describes a transdermal therapeutic system of the matrix type, where polyacrylate polymers are mixed in the with the hydrophobic base polymers of the active substance-containing polymer matrix. The hydrophobic base polymers may be selected from the group consisting of polysiloxanes, polyisobutylene, polyisoprene, styrene-diene-styrene block copolymer or mixtures thereof. The polyacrylate polymers are said to avoid the drawback of the supersaturation of the active substance in the TTS as a result of the addition of solvent, and to prevent recrystallization prior to absorption through the skin.
WO 94/23713 describes anti-inflammatory drugs based on phenylpropionic acid and phenylacetic acid for topical application, comprising combinations of lipophilic and hydrophilic excipients. No details are given of the mode of action or function of said excipients.